Molecular chaperones are a group of proteins that are catalytically involved in the folding or association of other proteins. Heat-shock protein 90 (HSP90) is a constitutively expressed molecular chaperone that governs the maturation of many regulatory factors that are key to cell growth and survival, as well as the maintenance of their stability. HSP90 is a molecular chaperone with a molecular weight of approximately 90,000, and is abundant in cells (approximately 1% to 2% of total soluble proteins) and uniformly distributed in the cytoplasm. HSP90 is known to interact with many molecules involved in the intracellular signal transduction system.
More specifically, it is known to be involved in the functional expression of not only signal transduction system proteins (for example, RAF-1, AKT/PKB, c-SRC, and ERBB2) and cell-cycle regulatory proteins (for example, CDK-1, CDK-4, mouse double minute 2, and TP53), but also apoptosis pathway proteins (for example, survivin and apoptosis protease activating factor 1) and such, and is suggested to be deeply involved in cell cycle regulation, and malignant transformation, growth, and survival signals. It is considered that inhibiting the function of HSP90 can at the same time inhibit the function of the above-mentioned proteins; therefore, HSP90 recently receives attention as a target of anticancer agents. Furthermore, there are reports that a number of genetic defects accumulate in the process of malignant transformation, and that in tumor cells, such modified proteins require chaperone activity more so than normal proteins. It is also reported that the expression level of HSP90 is increased in various cancers (Non-Patent Documents 1 and 2).
Accordingly, research and development of HSP90 inhibitors as anticancer agents is progressing. For example, clinical trials of single agent 17-allyamino-17-demethoxygeldanamycin (17-AAG) are carried out on advanced epithelial ovarian carcinoma, primary peritoneal carcinoma, metastatic renal cell carcinoma, von Hippel-Lindau disease, renal tumors, chemotherapy refractory breast cancer, advanced medullary carcinoma, differentiated thyroid carcinoma, metastatic melanoma, relapsed/refractory pediatric malignancies, and relapsed/refractory pediatric patients with solid tumors or leukemia.
Clinical trials are also performed to evaluate the concomitant use of 17-AAG with various anticancer agents. The diseases targeted by this concomitant use are solid tumors (concomitant agent: bortezomib), advanced solid tumors (concomitant agent: gemcitabine and cisplatin, docetaxel, paclitaxel), relapsed, refractory, and high-risk acute leukemia (concomitant agent: cytarabine), chronic myelogenous leukemia (concomitant agent: cytarabine, imatinib), fludarabine-refractory B-cell chronic lymphocytic leukemia (concomitant agent: fludarabine and rituximab), and hematologic malignancies (concomitant agent: bortezomib). Single-agent clinical trials for 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) are carried out on solid tumors and advanced solid tumors (Non-Patent Documents 1 and 2).
According to a press released by Infinity Pharmaceutical Inc., clinical trials on IPI-504, which is a 17-AAG analog, are performed on gastrointestinal tumor and multiple myeloma.
Additionally, research and development of Radicicol (KF-58333) (Non-Patent Document 3), purine derivatives such as PU24FCI (Patent Documents 1 and 2, and Non-Patent Document 4), pyrazole derivatives such as CCT-018159 (Patent Documents 3 to 5), pyrimidothiophene derivatives (Patent Document 6), 2-amino-4-phenylquinazoline derivatives (Patent Document 7), 2-amino-4-phenylpyrimidine derivatives (Patent Document 8), 2-amino-4-phenylthieno[2,3-d]pyrimidine derivatives (Patent Document 9) and such as low-molecular weight HSP90 inhibitors is under progress.
Cancer cells which are under stressful conditions such as abnormal protein expression, hypoxia, and nutritional starvation, are highly dependent on HSP90. Therefore, cancer cells are considered to show higher sensitivity towards HSP90 inhibitors. This is also supported by the pharmacokinetic analysis of 17-AAG in animal models, which is reported to show higher accumulation potential of 17-AAG in cancerous regions than in normal tissues. Accordingly, HSP90 inhibitors are expected to act specifically on cancer cells but not on normal cells, and may become a new type of anticancer agent not found in conventional anticancer agents. In addition, HSP90 inhibitors have been reported to enhance the efficacy of cytotoxic agents (Patent Document 10), which also makes them an interesting anticancer agent.
However, it has been pointed out that the use of geldanamycin derivatives and radicicol derivatives as pharmaceuticals is problematic in terms of their physical properties such as toxicity, stability, and water solubility. So far, there are no HSP90 inhibitors that have actually reached the market. Therefore, there has been a demand for a new compound class of HSP90 inhibitors that are different from these compounds.
In addition to anticancer and antitumor activity, HSP90 inhibitors have been reported to be useful as anti-inflammatory agents, anti-infectious-disease agents, agents for treating autoimmunity, agents for treating ischemia, and agents for enhancing nerve regeneration (Patent Documents 11-13). They are also reported to be useful as therapeutic agents for disorders, in which fibrogenesis can be induced, including pulmonary fibrosis, scleroderma, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, hepatic cirrhosis, keloid formation, interstitial nephritis, and such (Patent Document 14). Single-agent clinical trials of the aforementioned 17-AAG are also conducted for systemic mastocytosis.
On the other hand, several simple-structure compounds are known for 6-aryl-4-mercapto/oxy-(1,3,5)triazin/(1,3)pyrimidin-2-amine derivatives (Patent Document 15 and Non-Patent Document 5); however, neither anticancer effects nor inhibitory effects on HSP90 have been reported. Furthermore, the present inventors could not confirm anticancer effects in such simple-structure 6-aryl-4-mercapto/oxy-(1,3,5)triazin/(1,3)pyrimidin-2-amine derivatives.
There are other reports that 6-phenyl-N-phenyl-(1,3,5)triazin/(1,3)pyrimidin-2,4-diamine derivatives which are structurally similar to 6-aryl-4-mercapto/oxy-(1,3,5)triazin/(1,3)pyrimidin-2-amine derivatives have inhibitory effects on lysophosphatidic acid acyl transferase β (LPAAT-β) and are useful as anticancer agents (Patent Documents 16 and 17, and Non-Patent Document 6). However, the present inventors confirmed that such 6-phenyl-N-phenyl(1,3,5)triazin/(1,3)pyrimidin-2,4-diamine derivatives do not have inhibitory effects on HSP90. Currently, no LPAAT-β inhibitor is submitted to clinical trials as an anticancer agent, and anticancer effects of LPAAT-β inhibitors are limited to experimental results. Furthermore, LPAAT-β inhibitors cannot be expected to be useful as anticancer agents having the above-described HSP90-inhibiting effect, in particular, the unique effect of simultaneously acting on multiple promising targets.
[Patent Document 1] WO2002/036075
[Patent Document 2] WO2003/037860
[Patent Document 3] WO2003/055860
[Patent Document 4] WO2004/050087
[Patent Document 5] Japanese Patent Application Kokai Publication No. (JP-A) 2005-225787 (unexamined, published Japanese patent application)
[Patent Document 6] WO2005/021552
[Patent Document 7] WO2006/122631
[Patent Document 8] WO2006/123165
[Patent Document 9] WO2006/008503
[Patent Document 10] WO2002/036171
[Patent Document 11] WO2002/009696
[Patent Document 12] WO99/51223
[Patent Document 13] U.S. Pat. No. 6,210,974
[Patent Document 14] WO2002/002123
[Patent Document 15] JP-A S51-70780
[Patent Document 16] WO2003/037346
[Patent Document 17] US2004/0204386
[Non-patent Document 1] Future Oncol. (2005), 1(4), 529-540
[Non-patent Document 2] Expert Opin. on Emerging Drugs (2005), 10(1), 137-149
[Non-patent Document 3] Curr. Cancer Drug Targets. 2003 October, 3(5), 385-390
[Non-patent Document 4] Chem. Biol. 2001 March, 8(3), 289-299
[Non-patent Document 5] Journal fuer Praktische Chemie (Leipzig) (1980), 322(1), 55-68
[Non-patent Document 6] Bioorg. Med. Chem. Lett. (2004), 14, 2303-2308